Abstract 932: Conditional p53 loss in chondrocytes leads to osteosarcoma in mice
Authors: Xin Zhou, Zhaohui Xu, Yizheng Tu, Zhongting Zhang, Richard Gorlick
Journal: Cancer Research (2022)

Abstract Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults. Lack of a basic understanding of OS etiology, and lack of a sensitive method to detect pulmonary micro-metastases are major obstacles impeding meaningful therapeutic advancement. Here we report the generation of genetically engineered lineage-tracing mouse OS models, in which p53 expressions were conditionally deleted or mutated in chondrocytes, indicating that OS can originate from chondrocyte-derived osteoblastic-lineage cells. OS incidence peaks during puberty when rapid bone growth occurs. Longitudinal bone growth is achieved through endochondral ossification, a process sustained by growth plates - cartilage discs at the ends of long bones. As bone lengthening, growth plate chondrocytes go through proliferation, differentiation, and maturation in sequential steps to provide a continuous supply of cartilage scaffolds for ossification. Besides, mature chondrocytes residing at chondral-osteo junctions, are themselves an innate source of osteoblasts directly participating in bone formation. Not only there is a close link between OS incidence and growth plate activity, primary OS is most frequently localized at the growing ends of long bones, such as at proximal tibia, distal femurs, and proximal humerus. Given these associations, we hypothesize that mice harboring p53 deletion initiated in mature chondrocytes may develop osteosarcoma, and if so chondrocytes to osteoblasts transformation may be a vulnerable process to genome instability triggers. We generated various chondrocyte-Cre driven lineage-tracing reporter mouse models, in which either Col10a1-Cre or Acn-CreERT2 were Cre drivers to induce p53 deleted, R245W hot spot, and p53 deleted/Rbhet alleles. To date Col10a1-Cre/p53fxfx/Rosa-tomato (Xp53KO) mice developed osteosarcoma with 100% penetrance (n=32). The mean latency in days is 273.3 ± 60.5 (195-330), in a similar range of Osx-cre/p53fxfx mice by CR Walkley, etc. The OS from Xp53KO mice histologically resemble human OS and possessed osteogenic and adipogenic differentiation capacities in vitro. Most notably, the Xp53KO mice developed OS in long bones and spines, no cranium-facial OS was detected. Regarding OS distributions, our Xp53KO OS mice show the closest resemblance to that of humans, compared to previous genetically engineered mouse OS models. Additionally, the transplanted OS from Xp53KO mice showed good response to cyclophosphamide treatment (n=7, 15mg/kg), but not to topotecan (n=7, 0.6mg/kg), vincristine (n=7, 1mg/kg) and rapamycin (n=7, 5mg/kg) treatments, analogous to human OS. With reporter (tomato) expressions, we can trace and isolate the OS ancestry cells from the onsets of deletions to osteosarcoma genesis at any stages, as well as mutant cells in distant sites. Our OS models may unveil critical insights into the development of OS as well as its dissemination. Citation Format: Xin Zhou, Zhaohui Xu, Yizheng Tu, Zhongting Zhang, Richard Gorlick. Conditional p53 loss in chondrocytes leads to osteosarcoma in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 932.